Engineering B cells to treat and study human disease
Ueda, N. et al. Immunotherapy perspectives in the new era of B-cell editing. Blood Adv. 5, 1770–1779 (2021).
Google Scholar
Edelstein, J., Fritz, M. & Lai, S. K. Challenges and opportunities in gene editing of B cells. Biochem. Pharmacol. 206, 115285 (2022).
Google Scholar
Jeske, A. M., Boucher, P., Curiel, D. & Voss, J. Vector strategies to actualize B cell-based gene therapies. J. Immunol. 207, 755–764 (2021).
Google Scholar
Rogers, G. L. et al. Optimization of AAV6 transduction enhances site-specific genome editing of primary human lymphocytes. Mol. Ther. Methods Clin. Dev. 23, 198–209 (2021).
Google Scholar
Page, A., Hubert, J., Fusil, F. & Cosset, F.-L. Exploiting B cell transfer for cancer therapy: engineered B cells to eradicate tumors. Int. J. Mol. Sci. 22, 9991 (2021).
Google Scholar
Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6, 741–750 (2006).
Google Scholar
Hibi, T. & Dosch, H. M. Limiting dilution analysis of the B cell compartment in human bone marrow. Eur. J. Immunol. 16, 139–145 (1986).
Google Scholar
Amanna, I. J., Carlson, N. E. & Slifka, M. K. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007).
Google Scholar
Slifka, M. K., Antia, R., Whitmire, J. K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363–372 (1998).
Google Scholar
Gorzelany, J. A. & de Souza, M. P. Protein replacement therapies for rare diseases: a breeze for regulatory approval? Sci. Transl. Med. 5, 178fs10 (2013).
Samelson-Jones, B. J. & George, L. A. Adeno-associated virus gene therapy for hemophilia. Annu. Rev. Med. 74, 231–247 (2023).
Google Scholar
Srivastava, A. et al. Lentiviral gene therapy with CD34+ hematopoietic cells for hemophilia A. N. Engl. J. Med. 392, 450–457 (2025).
Google Scholar
Tiede, A. Half-life extended factor VIII for the treatment of hemophilia A. J. Thromb. Haemost. 13, S176–S179 (2015).
Google Scholar
Chen, H. H. et al. Enzyme replacement therapy for mucopolysaccharidoses; past, present, and future. J. Hum. Genet. 64, 1153–1171 (2019).
Chu, W. et al. Status and frontiers of Fabre disease. Orphanet J. Rare Dis. 20, 123 (2025).
Salabarria, S. M. et al. Advancements in AAV-mediated gene therapy for Pompe disease. J. Neuromuscul. Dis. 7, 15–31 (2020).
Google Scholar
Placci, M., Giannotti, M. I. & Muro, S. Polymer-based drug delivery systems under investigation for enzyme replacement and other therapies of lysosomal storage disorders. Adv. Drug Deliv. Rev. 197, 114683 (2023).
Google Scholar
Ozelo, M. C. et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N. Engl. J. Med. 386, 1013–1025 (2022).
Google Scholar
Pipe, S. W. et al. Gene therapy with etranacogene dezaparvovec for hemophilia B. N. Engl. J. Med. 388, 706–718 (2023).
Google Scholar
Mingozzi, F. & High, K. A. Overcoming the host immune response to adeno-associated virus gene delivery vectors: the race between clearance, tolerance, neutralization, and escape. Annu. Rev. Virol. 4, 511–534 (2017).
Google Scholar
Cunningham, S. C., Dane, A. P., Spinoulas, A. & Alexander, I. E. Gene delivery to the juvenile mouse liver using AAV2/8 vectors. Mol. Ther. 16, 1081–1088 (2008).
Google Scholar
Hill, T. F. et al. Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing. Mol. Ther. https://doi.org/10.1016/j.ymthe.2024.06.004 (2024).
Luo, B. et al. Engineering of α-PD-1 antibody-expressing long-lived plasma cells by CRISPR/Cas9-mediated targeted gene integration. Cell Death Dis. 11, 973 (2020).
Google Scholar
Moffett, H. F. et al. B cells engineered to express pathogen-specific antibodies protect against infection. Sci. Immunol. 4, eaax0644 (2019).
Google Scholar
Silacci, P., Mottet, A., Steimle, V., Reith, W. & Mach, B. Developmental extinction of major histocompatibility complex class II gene expression in plasmocytes is mediated by silencing of the transactivator gene CIITA. J. Exp. Med. 180, 1329–1336 (1994).
Google Scholar
Duan, M. et al. Understanding heterogeneity of human bone marrow plasma cell maturation and survival pathways by single-cell analyses. Cell Rep. 42, 112682 (2023).
Google Scholar
Young, D. J. et al. In vivo tracking of ex-vivo-generated 89Zr-oxine-labeled plasma cells by PET in a non-human primate model. Mol. Ther. https://doi.org/10.1016/j.ymthe.2024.12.042 (2024).
Hung, K. L. et al. Engineering protein-secreting plasma cells by homology-directed repair in primary human B cells. Mol. Ther. 26, 456–467 (2018).
Google Scholar
David, M. et al. Production of therapeutic levels of human FIX-R338L by engineered B cells using GMP-compatible medium. Mol. Ther. Methods Clin. Dev. 31, 101111 (2023).
Google Scholar
Liu, H. et al. A precision gene engineered B cell medicine producing sustained levels of active factor IX for hemophilia B therapy. Preprint at bioRxiv https://doi.org/10.1101/2025.04.06.647090 (2025).
Philippidis, A. Immusoft reports promising early data for lead candidate in MPS I. GEN—Genetic Engineering and Biotechnology News. www.genengnews.com/topics/drug-discovery/immusoft-reports-promising-early-data-for-lead-candidate-in-mps-i/ (2024).
Pipe, S. W. et al. Become-9: a phase 1/2 dose escalation and expansion study of be-101 for the treatment of adults with moderately severe or severe hemophilia B. Blood 144, 2593.1 (2024).
Rastogi, I. et al. Role of B cells as antigen presenting cells. Front. Immunol. 13, 954936 (2022).
Google Scholar
Okada, T. et al. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biol. 3, e150 (2005).
Song, W. & Craft, J. T follicular helper cell heterogeneity: time, space, and function. Immunol. Rev. 288, 85–96 (2019).
Google Scholar
Elsner, R. A. & Shlomchik, M. J. Germinal center and extrafollicular B cell responses in vaccination, immunity, and autoimmunity. Immunity 53, 1136–1150 (2020).
Google Scholar
Hartweger, H. et al. HIV-specific humoral immune responses by CRISPR/Cas9-edited B cells. J. Exp. Med. 216, 1301–1310 (2019).
Google Scholar
Huang, D. et al. B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models. Proc. Natl Acad. Sci. USA 117, 22920–22931 (2020).
Google Scholar
Huang, D. et al. Vaccine elicitation of HIV broadly neutralizing antibodies from engineered B cells. Nat. Commun. 11, 5850 (2020).
Google Scholar
Nahmad, A. D. et al. Engineered B cells expressing an anti-HIV antibody enable memory retention, isotype switching and clonal expansion. Nat. Commun. 11, 5851 (2020).
Google Scholar
Greiner, V. et al. CRISPR-mediated editing of the B cell receptor in primary human B cells. iScience 12, 369–378 (2019).
Google Scholar
Voss, J. E. et al. Reprogramming the antigen specificity of B cells using genome-editing technologies. eLife 8, e42995 (2019).
Rogers, G. L. et al. Reprogramming human B cells with custom heavy-chain antibodies. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-024-01240-4 (2024).
Yin, Y. et al. In vivo affinity maturation of mouse B cells reprogrammed to express human antibodies. Nat. Biomed. Eng. 8, 361–379 (2024).
Google Scholar
Wennhold, K. et al. Using antigen-specific B cells to combine antibody and T cell-based cancer immunotherapy. Cancer Immunol. Res. 5, 730–743 (2017).
Google Scholar
Lee-Chang, C. et al. Activation of 4-1BBL+ B cells with CD40 agonism and IFNγ elicits potent immunity against glioblastoma. J. Exp. Med. 218, e20200913 (2021).
Google Scholar
Wang, S. et al. B cell-based therapy produces antibodies that inhibit glioblastoma growth. J. Clin. Invest. 134, e177384 (2024).
Google Scholar
Winkler, J. et al. Adoptive transfer of donor B lymphocytes: a phase 1/2a study for patients after allogeneic stem cell transplantation. Blood Adv. 8, 2373–2383 (2024).
Google Scholar
Winkler, J. et al. GMP-grade generation of B-lymphocytes for adoptive immunotherapy in patients after allogeneic stem cell transplantation. Blood 120, 4352 (2012).
Winkler, J. et al. Adoptive transfer of purified donor-B-lymphocytes after allogeneic stem cell transplantation: results from a phase I/IIa clinical trial. Blood 128, 502 (2016).
Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D. & Anderton, S. M. B cells regulate autoimmunity by provision of IL-10. Nat. Immunol. 3, 944–950 (2002).
Google Scholar
Shen, P. et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507, 366–370 (2014).
Google Scholar
Parekh, V. V. et al. B cells activated by lipopolysaccharide, but not by anti-Ig and anti-CD40 antibody, induce anergy in CD8+ T cells: role of TGF-β 1. J. Immunol. 170, 5897–5911 (2003).
Google Scholar
Knippenberg, S. et al. Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naive/memory Breg ratio during a relapse but not in remission. J. Neuroimmunol. 239, 80–86 (2011).
Google Scholar
Blair, P. A. et al. CD19+CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity 32, 129–140 (2010).
Google Scholar
Flores-Borja, F. et al. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci. Transl. Med. 5, 173ra23 (2013).
Rosser, E. C. & Mauri, C. Regulatory B cells: origin, phenotype, and function. Immunity 42, 607–612 (2015).
Google Scholar
Shankar, S. et al. Ex vivo-expanded human CD19+TIM-1+ regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis. Nat. Commun. 13, 3121 (2022).
Google Scholar
Lee, K. M. et al. Suppression of allograft rejection by regulatory B cells induced via TLR signaling. JCI Insight 7, e152213 (2022).
Bao, Y. et al. Ex vivo-generated human CD1c+ regulatory B cells by a chemically defined system suppress immune responses and alleviate graft-versus-host disease. Mol. Ther. 32, 4372–4382 (2024).
Google Scholar
Zambidis, E. T., Kurup, A. & Scott, D. W. Genetically transferred central and peripheral immune tolerance via retroviral-mediated expression of immunogenic epitopes in hematopoietic progenitors or peripheral B lymphocytes. Mol. Med. 3, 212–224 (1997).
Google Scholar
El-Amine, M. et al. Mechanisms of tolerance induction by a gene-transferred peptide-IgG fusion protein expressed in B lineage cells. J. Immunol. 165, 5631–5636 (2000).
Google Scholar
Melo, M. E. F. et al. Gene transfer of Ig-fusion proteins into B cells prevents and treats autoimmune diseases. J. Immunol. 168, 4788–4795 (2002).
Google Scholar
Song, L. et al. Retroviral delivery of GAD-IgG fusion construct induces tolerance and modulates diabetes: a role for CD4+ regulatory T cells and TGF-β? Gene Ther. 11, 1487–1496 (2004).
Google Scholar
Lei, T. C. & Scott, D. W. Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins. Blood 105, 4865–4870 (2005).
Google Scholar
Wang, X. et al. Immune tolerance induction to factor IX through B cell gene transfer: TLR9 signaling delineates between tolerogenic and immunogenic B cells. Mol. Ther. 22, 1139–1150 (2014).
Google Scholar
Ahangarani, R. R. et al. In vivo induction of type 1-like regulatory T cells using genetically modified B cells confers long-term IL-10-dependent antigen-specific unresponsiveness. J. Immunol. 183, 8232–8243 (2009).
Calderón-Gómez, E. et al. Reprogrammed quiescent B cells provide an effective cellular therapy against chronic experimental autoimmune encephalomyelitis. Eur. J. Immunol. 41, 1696–1708 (2011).
Chen, D. et al. Novel engineered B lymphocytes targeting islet-specific T cells inhibit the development of type 1 diabetes in non-obese diabetic Scid mice. Front. Immunol. 14, 1227133 (2023).
Google Scholar
Pitner, R. A. et al. Blunting specific T-dependent antibody responses with engineered ‘decoy’ B cells. Mol. Ther. 32, 3453–3469 (2024).
Google Scholar
Luo, X. M. et al. Engineering human hematopoietic stem/progenitor cells to produce a broadly neutralizing anti-HIV antibody after in vitro maturation to human B lymphocytes. Blood 113, 1422–1431 (2009).
Google Scholar
Cheng, R. Y.-H. et al. Ex vivo engineered human plasma cells exhibit robust protein secretion and long-term engraftment in vivo. Nat. Commun. 13, 6110 (2022).
Google Scholar
He, W. et al. Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates. Immunity 56, 2408–2424.e6 (2023).
Google Scholar
Serafini, M., Naldini, L. & Introna, M. Molecular evidence of inefficient transduction of proliferating human B lymphocytes by VSV-pseudotyped HIV-1-derived lentivectors. Virology 325, 413–424 (2004).
Google Scholar
Janssens, W. et al. Efficiency of onco-retroviral and lentiviral gene transfer into primary mouse and human B-lymphocytes is pseudotype dependent. Hum. Gene Ther. 14, 263–276 (2003).
Google Scholar
Frecha, C. et al. Efficient and stable transduction of resting B lymphocytes and primary chronic lymphocyte leukemia cells using measles virus gp displaying lentiviral vectors. Blood 114, 3173–3180 (2009).
Google Scholar
Vamva, E. et al. A lentiviral vector B cell gene therapy platform for the delivery of the anti-HIV-1 eCD4-Ig-knob-in-hole-reversed immunoadhesin. Mol. Ther. Methods Clin. Dev. 28, 366–384 (2023).
Google Scholar
Levy, C. et al. Baboon envelope pseudotyped lentiviral vectors efficiently transduce human B cells and allow active factor IX B cell secretion in vivo in NOD/SCIDγc−/− mice. J. Thromb. Haemost. 14, 2478–2492 (2016).
Google Scholar
Bender, R. R. et al. Receptor-targeted Nipah virus glycoproteins improve cell-type selective gene delivery and reveal a preference for membrane-proximal cell attachment. PLoS Pathog. 12, e1005641 (2016).
Hamilton, J. R. et al. In vivo human T cell engineering with enveloped delivery vehicles. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-02085-z (2024).
Dobson, C. S. et al. Antigen identification and high-throughput interaction mapping by reprogramming viral entry. Nat. Methods 19, 449–460 (2022).
Google Scholar
Yu, B. et al. Engineered cell entry links receptor biology with single-cell genomics. Cell 185, 4904–4920.e22 (2022).
Google Scholar
Takano, K.-A. et al. Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo. Mol. Ther. 32, 1311–1327 (2024).
Google Scholar
Ou, T. et al. Reprogramming of the heavy-chain CDR3 regions of a human antibody repertoire. Mol. Ther. 30, 184–197 (2022).
Google Scholar
Johnson, M. J., Laoharawee, K., Lahr, W. S., Webber, B. R. & Moriarity, B. S. Engineering of primary human B cells with CRISPR/Cas9 targeted nuclease. Sci. Rep. 8, 12144 (2018).
Selvaraj, S. et al. High-efficiency transgene integration by homology-directed repair in human primary cells using DNA-PKcs inhibition. Nat. Biotechnol. 42, 731–744 (2024).
Google Scholar
Sheridan, C. B cells as drug factories. Nat. Biotechnol. 42, 823–826 (2024).
Google Scholar
Hackett, P. B. & Essner, J. Integration-site directed vector systems. US patent US7919583B2 (2005).
Laoharawee, K. et al. Genome engineering of primary human B cells using CRISPR/Cas9. J. Vis. Exp. https://doi.org/10.3791/61855 (2020).
Giguère, S. et al. Antibody production relies on the tRNA inosine wobble modification to meet biased codon demand. Science 383, 205–211 (2024).
Christie, S. M., Fijen, C., & Rothenberg, E. V(D)J recombination: recent insights in formation of the recombinase complex and recruitment of DNA repair machinery. Front. Cell Dev. Biol. 10, 886718 (2022).
Nahmad, A. D. et al. In vivo engineered B cells secrete high titers of broadly neutralizing anti-HIV antibodies in mice. Nat. Biotechnol. 40, 1241–1249 (2022).
Google Scholar
Russell, D. M. et al. Peripheral deletion of self-reactive B cells. Nature 354, 308–311 (1991).
Google Scholar
Abbott, R. K. et al. Precursor frequency and affinity determine B cell competitive fitness in germinal centers, tested with germline-targeting HIV vaccine immunogens. Immunity 48, 133–146.e6 (2018).
Google Scholar
Dosenovic, P. et al. Anti–HIV-1 B cell responses are dependent on B cell precursor frequency and antigen-binding affinity. Proc. Natl Acad. Sci. USA 115, 4743–4748 (2018).
Google Scholar
Tokatlian, T. et al. Enhancing humoral responses against HIV envelope trimers via nanoparticle delivery with stabilized synthetic liposomes. Sci. Rep. 8, 16527 (2018).
Wagar, L. E. et al. Modeling human adaptive immune responses with tonsil organoids. Nat. Med. 27, 125–135 (2021).
Google Scholar
Pan, A. et al. In vivo affinity maturation of the CD4 domains of an HIV-1-entry inhibitor. Nat. Biomed. Eng. 8, 1715–1729 (2024).
Google Scholar
Buerstedde, J.-M., Alinikula, J., Arakawa, H., McDonald, J. J. & Schatz, D. G. Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. PLoS Biol. 12, e1001831 (2014).
O’Connor, B. P. et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199, 91–98 (2004).
Wallweber, H. J. A., Compaan, D. M., Starovasnik, M. A. & Hymowitz, S. G. The crystal structure of a proliferation-inducing ligand. April. J. Mol. Biol. 343, 283–290 (2004).
Google Scholar
Lapidot, T. Mechanism of human stem cell migration and repopulation of NOD/SCID and B2mnull NOD/SCID mice. Ann. N. Y. Acad. Sci. 938, 83–95 (2001).
Google Scholar
Hargreaves, D. C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45–56 (2001).
Google Scholar
Chatterjee, S., Behnam Azad, B. & Nimmagadda, S. The intricate role of CXCR4 in cancer. Adv. Cancer Res. 124, 31–82 (2014).
Google Scholar
Vonderheide, R. H., Tedder, T. F., Springer, T. A. & Staunton, D. E. Residues within a conserved amino acid motif of domains 1 and 4 of VCAM-1 are required for binding to VLA-4. J. Cell Biol. 125, 215–222 (1994).
Google Scholar
Newham, P. et al. Α4 integrin binding interfaces on VCAM-1 and MAdCAM-1. J. Biol. Chem. 272, 19429–19440 (1997).
Google Scholar
Benet, Z., Jing, Z. & Fooksman, D. R. Plasma cell dynamics in the bone marrow niche. Cell Rep. 34, 108733 (2021).
Google Scholar
Nguyen, D. C. et al. Author correction: factors of the bone marrow microniche that support human plasma cell survival and immunoglobulin secretion. Nat. Commun. 10, 372 (2019).
Roldán, E., García-Pardo, A. & Brieva, J. A. VLA-4-fibronectin interaction is required for the terminal differentiation of human bone marrow cells capable of spontaneous and high rate immunoglobulin secretion. J. Exp. Med. 175, 1739–1747 (1992).
Fiorillo, M. T., Cabibbo, A., Iacopetti, P., Fattori, E. & Ciliberto, G. Analysis of human/mouse interleukin-6 hybrid proteins: both amino and carboxy termini of human interleukin-6 are required for in vitro receptor binding. Eur. J. Immunol. 22, 2609–2615 (1992).
Google Scholar
Neuber, T. et al. Characterization and screening of IgG binding to the neonatal Fc receptor. MAbs 6, 928–942 (2014).
Ober, R. J., Radu, C. G., Ghetie, V. & Ward, E. S. Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies. Int. Immunol. 13, 1551–1559 (2001).
Google Scholar
Andersen, J. T., Daba, M. B., Berntzen, G., Michaelsen, T. E. & Sandlie, I. Cross-species binding analyses of mouse and human neonatal Fc receptor show dramatic differences in immunoglobulin G and albumin binding. J. Biol. Chem. 285, 4826–4836 (2010).
Li, F. et al. Mouse strains influence clearance and efficacy of antibody and antibody-drug conjugate via Fc-FcγR interaction. Mol. Cancer Ther. 18, 780–787 (2019).
Google Scholar
Oldham, R. J. et al. FcγRII (CD32) modulates antibody clearance in NOD SCID mice leading to impaired antibody-mediated tumor cell deletion. J. Immunother. Cancer 8, e000619 (2020).
Yu, H. et al. A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production. Blood 129, 959–969 (2017).
Google Scholar
Li, Y. et al. A human immune system mouse model with robust lymph node development. Nat. Methods 15, 623–630 (2018).
Google Scholar
Chupp, D. P. et al. A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses. Nat. Immunol. https://doi.org/10.1038/s41590-024-01880-3 (2024).
Sun, K. & Liao, M. Z. Clinical pharmacology considerations on recombinant adeno-associated virus-based gene therapy. J. Clin. Pharmacol. 62, S79–S94 (2022).
Google Scholar
Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).
Google Scholar
Tsuchida, C. A. et al. Mitigation of chromosome loss in clinical CRISPR–Cas9-engineered T cells. Cell 186, 4567–4582.e20 (2023).
Google Scholar
Lazar, N. H. et al. High-resolution genome-wide mapping of chromosome-arm-scale truncations induced by CRISPR-Cas9 editing. Nat. Genet. 56, 1482–1493 (2024).
Google Scholar
Nahmad, A. D. et al. Frequent aneuploidy in primary human T cells after CRISPR–Cas9 cleavage. Nat. Biotechnol. 40, 1807–1813 (2022).
Google Scholar
Zhang, T.-T. et al. BCR signaling is required for posttransplant lymphoproliferative disease in immunodeficient mice receiving human B cells. Sci. Transl. Med. 16, eadh8846 (2024).
Google Scholar
Stockfelt, M., Teng, Y. K. O. & Vital, E. M. Opportunities and limitations of B cell depletion approaches in SLE. Nat. Rev. Rheumatol. 21, 111–126 (2025).
Gargett, T. & Brown, M. P. The inducible caspase-9 suicide gene system as a “safety switch†to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front. Pharmacol. 5, 235 (2014).
Dunkelberger, J. R. & Song, W.-C. Complement and its role in innate and adaptive immune responses. Cell Res. 20, 34–50 (2010).
Google Scholar
Ma, A. D. & Carrizosa, D. Acquired factor VIII inhibitors: pathophysiology and treatment. Hematol. Am. Soc. Hematol. Educ. Program 2006, 432–437 (2006).
Jawa, V. et al. T-cell dependent immunogenicity of protein therapeutics pre-clinical assessment and mitigation-updated consensus and review 2020. Front. Immunol. 11, 1301 (2020).
Google Scholar
Sabatino, D. E. et al. Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors. Mol. Ther. 19, 442–449 (2011).
Google Scholar
Annoni, A. et al. Liver gene therapy by lentiviral vectors reverses anti-factor IX pre-existing immunity in haemophilic mice. EMBO Mol. Med. 5, 1684–1697 (2013).
Google Scholar
Chand, D. et al. Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J. Hepatol. 74, 560–566 (2021).
Google Scholar
Manno, C. S. et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med. 12, 342–347 (2006).
Google Scholar
Gallo-Penn, A. M. et al. Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs. Blood 97, 107–113 (2001).
Google Scholar
Grauwet, K. et al. Stealth transgenes enable CAR-T cells to evade host immune responses. J. Immunother. Cancer 12, e008417 (2024).
Wang, B. et al. Generation of hypoimmunogenic T cells from genetically engineered allogeneic human induced pluripotent stem cells. Nat. Biomed. Eng. 5, 429–440 (2021).
Google Scholar
Hu, X. et al. Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-01784-x (2023).
Gupta, P., Alheib, O. & Shin, J.-W. Towards single cell encapsulation for precision biology and medicine. Adv. Drug Deliv. Rev. 201, 115010 (2023).
Google Scholar
Kershaw, M. H. et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006).
Google Scholar
Hartweger, H. et al. Gene editing of primary rhesus macaque B cells. J. Vis. Exp. https://doi.org/10.3791/64858 (2023).
Vamva, E. et al. An optimized measles virus glycoprotein-pseudotyped lentiviral vector production system to promote efficient transduction of human primary B cells. STAR Protoc. 3, 101228 (2022).
Google Scholar
Yu-Hong Cheng, R. et al. Generation, expansion, gene delivery, and single-cell profiling in rhesus macaque plasma B cells. Cell Rep. Methods 4, 100878 (2024).
Google Scholar
Ishikawa, M. et al. Bone marrow plasma cells require P2RX4 to sense extracellular ATP. Nature 626, 1102–1107 (2024).
Google Scholar
Van Dam, M. et al. Structure–function analysis of interleukin-6 utilizing human/murine chimeric molecules. Involvement of two separate domains in receptor binding. J. Biol. Chem. 268, 15285–15290 (1993).
